2025 Sequencing Strategies for Population and Cancer Epidemiology Studies (SeqSPACE) : Submission #4

Submission information
Submission Number: 4
Submission ID: 149905
Submission UUID: 2e9a9c5c-20b6-4418-8458-3d44a41a7e68
Submission URI: /egrp/seqspaceabstracts

Created: Wed, 08/27/2025 - 00:06
Completed: Wed, 08/27/2025 - 00:06
Changed: Wed, 08/27/2025 - 00:06

Remote IP address: 10.208.28.36
Submitted by: Anonymous
Language: English

Is draft: No
First Name Katherine
Middle Initial Anne
Last Name Lawson-Michod
Degree(s) Ph.D. MPH
Position/Title/Career Status Postdoctoral Fellow
Organization Fred Hutchinson Cancer Center
Email klawsonm@fredhutch.org
Abstract Title Homologous recombination deficiency and survival in ovarian high-grade serous carcinoma by self-reported race
Abstract Summary Survival after a diagnosis of high-grade serous ovarian carcinoma (HGSC) is worse for Black individuals compared to White individuals. Current understanding of HGSC molecular heterogeneity, including homologous recombination deficiency (HRD)—the most common etiologic pathway—is based largely on the evaluation of tumors from White patients. We leveraged newly generated whole-exome sequencing and existing RNASeq from 272 Black individuals with HGSC to identify significantly mutated genes, mutational signatures, and HRD features. We evaluated the reliability of our data by comparing to the Cancer Genome Atlas and confirmed our findings by comparing the data from Black patients with those from 123 White patients with identical tissue collection and processing. Finally, we incorporated epidemiologic data to annotate variants of uncertain significance (VUS) and assess whether population differences in HRD contribute to differences in survival. Despite technical differences, mutations and variant classifications for major HGSC genes were nearly identical across populations. However, de novo analysis identified novel significantly mutated genes, including the oncogene KRAS and a potential tumor suppressor OBSCN in Black patients. We also observed that a greater proportion of variants in homologous recombination genes were unannotated/VUS among Black individuals; however, these variants correlated with HRD scarring and a family history of breast or ovarian cancer suggesting some may be pathogenic. HRD was associated with a 32% reduced risk of death in Black individuals compared with a 62% reduction in White individuals. Overall, most HGSC tumor features are similar across Black and White individuals with HGSC, and it is unlikely that population differences in tumor features explain survival differences. Still, clinically relevant differences exist including a higher prevalence of certain tumor suppressor genes and a higher proportion of VUS among Black individuals which may hinder referral to care and contribute to worse outcomes. These findings underscore the need for diverse representation in genomics research.